5,11-dihydroindolo(3,2-c)(2,1)-benzothiazine-6,6-dioxide compounds



United States Patent 7 Claims ABSTRACT OF THE DISCLOSURE S-di-loweralkylaminoalkyl-5,ll-dihydroindolo[3,2 c][2,1]benzothiazine-6,6-dioxides are prepared by reacting aphenylhydrazine with 3,4-dihydro-4-oxosulfostyril, cyclizing theresulting phenylhydrazone to give a 5,11-dihydroindolo[3,2-c][2,1]benzothiazine-6,6-dioxide intermediate and then reacting with aN,N-dilower alkyl-haloalkylamine. The products have hypotensive anddiuretic activity.

This application is a continuationin-part of Ser. No. 549,476 filed May12, 1966, now abandoned.

This invention relates to new S-di-lower alkylaminoalkyl 5,11dihydroindolo[3,2-c] [2,l]benz0thiazine-6,6- dioxide compounds havingpharmacodynamic activity, in particular, hypotensive activity and,especially when the S-di-lower alkylaminoalkyl group is a S-di-loweralkylaminoethyl group, diuretic activity. The hypotensive activity isdemonstrated by administration intravenously at doses of about 5-10 mg./kg. to dogs anesthetized with pentobarbital. The diuretic activity isdemonstrated by oral administration to rats at doses of about 1530 mg./kg. in a test for antagonism of anti-diuretic hormone in whichanti-diuretic hormone in doses of 1 m;/./ 100 g. body weight isadministered subutaneously and water and alcohol loads are administered.This invention also relates to intermediates for preparing thesepharmacodynamically active compounds.

The 5 di lower alkylaminoalkyl-5,ll-dihydroindolo[3,2-c][2,1]benzothiazine-6,6-dioxide compounds of this invention arerepresented by the following formula:

FORMULA I 7 (S): R3 8 @i 9 11 R2 when:

Y is hydrogen, halogen or trifiuoromethyl; R is hydrogen or lower alkyl;

R and R are lower alkyl and n is 2 or 3.

The pharmacodynamically active compounds of this invention have thebasic S-di-lower alkylaminoalkyl-5,1ldihydroindolo 3,2-c][2,1]benzothiazine-6,6-dioxide structure of Formula 1. However, it isapparent to one skilled in the art that obvious nuclear substituents maybe incorporated on the benzenoid ring of the benzothiazine nucleus. Suchsubstituents, which are known to the art, are halogen, trifiuoromethyl,lower alkyl, amino, hydroxy, lower alkoxy, lower alkylthio ormethylenedioxy. Obvious nuclear substituents, which are known to theart, such as lower alkyl, hydroxy, lower alkoxy or methylenedioxy may beincorporated on the benzenoid ring of the indolo nucleus, for example,in place of the indicated Y substituents. These substituted compoundsare useful as are the parent compounds.

An advantageous compound of this invention is represented by Formula Iwhen Y is hydrogen, R and R are methyl and n is 2.

This invention also includes pharmaceutically acceptable salts of thecompounds of Formula I formed with nontoxic organic and inorganic acids.Such salts are easily prepared by methods known to the art. The base isreacted with either the calculated amount of organic or inorganic acidin aqueous miscible solvent, such as acetone or ethanol, with isolationof the salt by concentration and cooling or an excess of the acid inaqueous immiscible solvent, such as ethyl ether or chloroform, with thedesired salt separating directly. Exemplary of such organic salts arethose with maleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicylic, citric, gluconic, lactic, malic,mandelic, innamic, citraconic, aspartic, stearic, palmitic, itaconic,glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophyllineacetic acids as well as with the 8-halotheophyllines, for example, 8-bromotheophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitricacids. Of course, these salts may also be prepared by the classicalmethod of double decomposition of appropriate salts which is well knownto the art.

The new compounds useful as intermediates in the preparation of thecompounds of Formula I and further objects of this invention arerepresented by the following formula:

FORMULA II The term Y is as defined in Formula I.

Compounds having the basic 5,l1-dihydroindolo[3,2-c][2,1]-benzothiazine-6,6-dioxide structure of Formula II may havesubstituents such as halogen, trifiuoromethyl, lower alkyl, amino,hydroxy, lower alkoxy, lower alkylthio or methylenedioxy incorporated onthe benzenoid ring of the benzothiazine nucleus and substituents such aslower alkyl, hydroxy, lower alkoxy or methylenedioxy incorporated on thebenzenoid-ring of the indolo nucleus, for example, in place of theindicated Y substituents. These substituted compounds are used, asdescribed herebelow to prepare pharmacodynamically active compoundswhich have the basic structure of Formula I and which arecorrespondingly substituted.

The terms lower alkyl and lower alkoxy where used herein denote groupshaving 1-4, preferably 1-2, carbon atoms and halogen denotes chloro,bromo and fluoro.

Compounds of this invention are prepared by the following procedure:

s s NHNH: \N/ 2 \N/ 2 It i The term R is lower alkyl and the term Y, R Rand n are as defined above.

According to the above procedure, a phenylhydrazine is reacted with3,4-dihydro-4-oxosulfostyril to give the phenylhydrazone. The reactionis preferably carried out in an inert solvent such as a lower alkanol inthe presence of acid such as hydrochloric or glacial acetic acid atelevated temperature, conveniently at reflux temperature.

The resulting hydrazone is cyclized by treating with an excess ofpolyphosphoric acid at elevated temperature, for example at about 85-l50C., or trifiuoroacetic acid at about 50 to 70 C. to give the5,l1-dihydroindolo[3,2- c] [2,1]benzothiazine-6,6-dioxide intermediate.This intermediate is treated with an equimolar amount or about a -15%excess of a base such as sodium hydride or sodium methoxide in an inertsolvent and the resulting mixture is heated with a N,N-di-loweralkyl-haloalkylamine at about 85-l25 C. to give the S-di-loweralkylaminoalkyl- 5,11 dihydroindolo[3,2-c][2,1]benzothiazine-6,6-dioxide.

Alternatively, the 3,4-dihydro-4-oxosulfostyril starting material may betreated with a base such as sodium hydride or sodium methoxide in aninert solvent and the resulting mixture heated with a N,N-di-loweralkyl-haloalkylamine to give a l-di-loweralkylaminoalkyl-3,4-dihydro-4-oxo-sulfostyril. Reacting this sulfostyrilwith a phenylhydrazine to form the phenylhydrazone and then cyclizing asdescribed above gives the 5-di-lower alkylaminoalkyl 5,11 dihydroindolo[3,2-c] [2,l]benzothiazine-6,6- dioxide.

The compounds of Formula I in which R is lower alkyl are prepared byreacting the compounds in which R is hydrogen with a base such as sodiumhydride or butyl lithium and then with a lower alkyl halide in an inertsolvent such as ether or dimethylsulfoxide at elevated temperature.

Substituents such as lower alkyl, hydroxy, lower alkoxy ormethylenedioxy may be present on the phenyl ring of the phenylhydrazinestarting material, for example, in place of the indicated Y Substituentsand Substituents such as halogen, trifluoromethyl, lower alkyl, amino,hydroxy, lower alkoxy, lower alkylthio or methylenedioxy may be presenton the benzenoid ring of the 3,4-dihydro-4-oxosulfostyril startingmaterial in the above procedure (I) to give the correspondinglysubstituted S-di-lower alkyl- 4 aminoalkyl 5,11 dihydroindolo[3,2- c][2,l]benzothiazine-6,6-dioxides.

The 3,4-dihydro-4-oxosulfostyril starting material is prepared asfollows:

in which R is lower alkyl.

According to the above procedure aniline is condensed with a lower alkylchlorosulfonylacetate to give a lower alkyl N-phenylsulfamoylacetatewhich is converted by heating with an alkali metal hydroxide such assodium hydroxide to the N-phenylsulfamoylacetic acid. Cyclizing in anexcess of polyphosphoric or sulfuric acid at about -150 C. ortrifluoroacetic anhydride at 0100 C. gives 3,4-dihydro-4-oxosulfostyril.

In the above procedure, Substituents such as halogen, trifiuoromethyl,lower alkyl, nitro, hydroxy, lower alkoxy, lower alkylthio ormethylenedioxy may be present on the phenyl ring of the aniline startingmaterial to prepare the correspondingly substituted3,4-dihydro-4-oxosulfostyrils.

3,4-dihydro-4-oxosulfostyrils having an amino substituent on thebenzenoid ring are prepared by reducing the correspondingnitro-substituted 3,4-dihydro-4-oxosulfostyril by hydrogenation in alower alkanol at room temperature using palladium-on-carbon as catalyst.

The compounds of Formula I may be administered in conventional dosageforms by incorporating an appropriate dose of the compound withpharmaceutical carriers according to accepted pharmaceutical practices.

The following examples are not limiting but are illustrative of thecompounds of this invention and the processes for their preparation.

Example 1 A concentrated solution of 40.0 g. of methylchlorosulfonylacetate in ether is added to a solution of 45.3 g. ofaniline in 500 ml. of ether at C. After stirring at room temperature foran hour, the suspension is filtered and the filtrate is concentrated togive methyl N-phenylsulfomoylacetate.

The above prepared ester g.) and 77 ml. of 10% sodium hydroxide solutionare heated at reflux for three hours. The mixture is cooled, acidifiedand extracted with chloroform to give N-phenylsulfamoylacetic acid.

A mixture of 10 g. of the above prepared acid and 200 g. ofpolyphosphoric acid is heated to 125 C. and maintained at thattemperature for 5 minutes with stirring. The mixture is cooled, thentreated with ice water and filtered to give3,4-dihydro-4-oxosulfostyril.

Fifty grams of 3,4-dihydro-4-oxosulfostyril is warmed on a steam bathwith 625 ml. of ethanol until all the sulfostyril is in solution. Tothis solution is added 50 ml. of phenylhydrazine and 12.5 ml. of glacialacetic acid and the resulting solution is refluxed with stirring for 15minutes. The mixture is heated for about 15 minutes on a steam bath,then chilled and filtered. The solid material is washed with isopropylether to give the phenylhydrazone of 3,4-dihydro-4-oxosulfostyril.

A mixture of 33 g. of the above prepared phenylhydrazone is stirred witha large excess of polyphosphoric acid, then heated on a steam bath withoccasional stirring for about 35 minutes. The mixture is then pouredonto ice-Water, then made strongly basic with sodium hydroxide solutionand filtered. The filtrate is acidified with concentrated hydrochloricacid and filtered to give 5,11-dihydroindolo [3 ,2-c][2,1]benzothiazine-6,6-dioxide.

A dry benzene solution of 12.2 g. of N,'N-dimethyl-2- chloroethylamineis added with stirring to a solution of 10.8 g. of5,11-dihydroind0lo[3,2-c] [2,1]benzothiazine-6,- 6-dioxide in 100 ml. ofdry dimethylsulfoxide and 2.0 g. of a 55% dispersion of sodium hydridein mineral oil and the resulting mixture is refluxed for 23 hours withstirring, then filtered. The filtrate is concentrated, poured into 300ml. of water and the resulting mixture is extracted With ether. Theether extracts are washed with water, then dried over magnesium sulfateand evaporated to dryness. To the residue is added 75 ml. of ether and25 ml. of ethanol. Filtering gives5-(Z-dimethylaminoethyl)-5,1l-dihydroindolo [3 ,2-c][2,1]benzothiazine-6,6-dioxide.

One gram of the above prepared base suspended in water is treated withdilute hydrochloric acid. The mixture is heated until solution iscomplete and then chilled and filtered to give 5(Z-dimethylaminoethyl)-5,1l-dihyclroindolo 3,2-c][2,1]benzothiazine-6,6-dioxide hydrochloride.

Example 2 To 11.6 g. of 5,1l-dihydroindolo[3,2-c][2,1]benzothiazine-6,6-dioxide, prepared as in Example 1, in 100 ml. ofdry di-methylsulfoxide is added with stirring 2.0 g. of a 55 dispersionof sodium hydride in mineral oil. After the hydrogen evolution stops, asolution of 12.15 g. of dimethyl-3-chloropropylamine in 100 ml. ofanhydrous benzene is added dropwise, with stirring, over a 10' minuteperiod and the resulting mixture is refluxed for 21 hours with stirring.The mixture is filtered and the filtrate is concentrated. The residue ispoured into 300 ml. of Water and the resulting mixture is extracted withether. The ether extracts are Washed with water and dried over magnesiumsulfate. The ether is evaporated and the residue is dissolved in dryether containing a few drops of methanol. Ethereal hydrochloric acid isadded and the mixture is chilled and decanted to give a semi-solidmaterial which is slurried with hot acetone. Chilling, filtering andrecrystallizing from ethanol containing a small amount of methanol gives5 (3 dimethylaminopropyl)-5,1l-dihydroind0lo[3,2-c] [2,1]benzot-hiazine6,6 dioxide hydrochloride.

Example 3 Using, in place of aniline in the procedure of Example 1, thefollowing:

p-chloroaniline o-chloroaniline m-bromoaniline p-fiuoroanilinep-trifluoromethylaniline p-ethylaniline p-aminophenol p-anisidinep-methylthioaniline 4-aminopyrocatechol 3 ,4-dimethoxyaniline 3,4-methylenedioxyaniline the following sulfostyrils are obtained:

6-chloro-3,4-dihydro-4-oxosulfostyril8-ohloro-3,4-dihydro-4-oxosulfostyril 5- (and 7)bromo-3,4-dihydro-4-oxosulfostyril 6-fiuoro-3,4-dihydro-4-oxosulfostyril3,4-dihydr0-4-oxo6-trifluoromethylsulfostyril6-ethyl-3,4-dihydro-4-oxosulfostyril6-amino-3,4-dihydro-4-oxosulfostyril3,4-dihydro-6-methoxy-4-oxosulfostyril3,4-dihydro-6-methylthio-4-oxosulfostyril 3 ,4-dihydro-5 ,6- (and 6,7dihydroxy-4-oxosulfostyril 3,4-dihydro-5,6- (and 6,7)dimethoxy-4-oxosulfostyril 3,4 dihydro 5,6 (and6,7)methylenedioxy-4-oxosulfostyril.

Using each of the above prepared sulfostyrils in the procedure ofExample 1, the following products are obtained, respectively:

2-chloro-5-(Z-dimethylaminoethyl)-5,1l-dihydroindolo[3,2-c][2,1]benzothiazine6,6-dioxide4-chloro-5-(Z-dimethylaminoethyl)-5,1l-dihydroindolo[3,2-c][2,1]benzothiazine-6,6-dioxide 1- (and 3)bromo-S-(Z-dirnethylaminoethyl)-5,1 1-

dihydroindolo[3,2-c] [2,1]benzothiazine-6,6-dioxide5-(Z-dimethylaminoethyl)-2-fluoro-5,1l-dihydroindolo[3,2-c][2,l]benzothiazine-6,6-dioxideS-(Z-dimethylaminoethyl)-5,11-dihydro-2-trifiuoromethylindolo[3,2-c][2,1]benzothiazine-6,6-dioxide 5 (Z-dimethylaminoethyl -2-ethyl-5 1l-dihydroindolo- [3,2-c] [2,1]benzothiaZine-6,6-dioxide 5-(Z-dimethylaminoethyl) -5 11-dihydro-2-hydroxyindolo [3,2-c][2,1]benzothiazine-6,6-dioxicle 5- (2-dimethylaminoethyl)-5 ,1l-dihydro-Z-methoxyindolo[3,2-c] [2,1]benzothiazine-6,6-dioxide 52-dimethylaminoethyl -5 ,1 1-dihydro-2-methylthioihdolo [3,2-c][2,1]benzothiazine-6,6-dioxide 5- (Z-dimethylaminoethyl)-5,11-dihydro-1,2(and 2,3 dimethoxyindolo[3,2-c][2,1]benzothiazine-6,6-dioxide 5- Z-dimethyla-minoethyl -5, 1l-dihydro-l ,2- (and 2,3

dihydroxyindolo [3,2-c] [2,1] benzothi azine-6,6-dioxideS-(Z-dimethylaminoethyl)-5, 1 1-dihydro1,2- (and 2,3

methylenedioxyindoloI 3,2-c] [2, l benz0thiazine-6,6- dioxide.

The above prepared 1- (and 3)bromo compounds are separated into thel-bromo and 3-bromo isomers by chromatography on alumina using methylenechloride as the solvent. Similarly, the 1,2- and 2,3-dimethoxy,-dihydroxy and -methylenedioxy isomers are separated.

One gram of 2-chloro-5-(Z-dimethylaminoethyl)-5,1ldihydroindolo[3,2-c][2,l]benzothiazine 6,6 dioxide in ether is treated with hydrogen bromideto give the hydrobromide salt.

Example 4 By the procedure of Example 1, the following compounds areconverted to the substituted 3,4-dihydro-4-oxosulfostyrils:

m-butylaniline 3,4-dichloroani1ine 3,4-dibutoxyaniline p-toluidinep-butylthioaniline Using these sulfostyrils and p-hydrazinophenol in theprocedure of Example 1, the products are, respectively:

1- (and 3)butyl-5-(Z-dimethylaminoethyl)-5,11-

dihydro-S-hydroxyindolo [3,2-c] [2,11benzothiazine- 6,6-dioxide 1,2-(and 2,3) dichloro-S-(2-dimethylaminoethyl)-S, 11-dihydro-S-hydroxyindolo 3,2-c] [2,1]benzothiazine- 6,6-dioxide 1,2-( and2,3 dibutoxy-S- (Z-dimethylaminoaminoethyl) -5, ll-dihydro-S-hydroxyindolo 3,2-c] [2,1]- benzothiazine-6,6-dioxide-(2-dimethylaminoethyl)-5,1l-dihydro-8-hydroxy-2- methylindolo 3,2-c][2,1] benzothiazine-6,6-dioxide2-butylthio-5-(Z-dimethylaminoethyl)-5,1l-dihydro-8- hydroxyindolo[ 3,2-c] [2,1]benzothiazine-6,6dioxide.

The above prepared mixture of 1,2- and 2,3-dichloroisomers is separatedby chromatography on alumina using methylene chloride as the solvent.Similarly, the mixture of 1,2- and 2,3-dibutoxy isomers is separated.

Example 5 By the procedure of Example 1, using p-nitroaniline, 5 (2dimethylaminoethyl) 5,11 dihydro 2 nitroindolo[3,2-c][2,1]benzothiazine-6,6-dioxide is obtained. Hydrogenating this 2-nitrocompound in ethyl acetate at room temperature using palladium-on-carbonas catalyst gives2-amino-5-(2-dimethylaminoethyl)-5,1l-dihydroindolo[3,2-c][2,1]benzothiazine-6,6-dioxide.

Example 6 By the procedure of Example 1, using 3,4-dihydro-4-oxosulfostyril and the following substituted phenylhydrazines:

p-chlorophenylhydrazine p-fluorophenylhydrazinep-trifluorornethylphenylhydrazine m-tolylhydrazinep-methoxyphenylhydrazine o-methoxyphenylhydrazine3,4-dichlorophenylhydrazine 3,4-methylenedioxyphenylhydrazine thefollowing products are obtained, respectively:

8 -chloro-5-(Z-dimethylaminoethyl)-5,11-dihydroindolo 3,2-c] [2,1]benzothiazine-6,6-dioxide 5 Z-dimethylaminoethyl) -8-fiuoro-5 ,1l-dihydroindolo 3,2-c] [2,1]benzothiazine-6,6-dioxide5-(2-dimethylaminoethyl)-5,1l-dihydro-S-trifiuoromethylindolo [3 ,2-c][2,1]benzothiazine-6,6-dioxide5-(2-dimethylaminoethyl)-5,11-dihydro-7-(and 9)- methylindolo [3,2-c][2,1] benzothiazine-6,6-dioxideS-(Z-dimethylaminoethyl)-5,11-dihydro-8-methoxyindolo 3,2-c] [2, 1]benzothiazine-6,6-dioxide 5 Z-dimethylaminoethyl) -5 ,1 l-dihydro-IO-methoxyindolo [3 ,2-c] [2,1]benzothiazine-6,6-dioxide 7,8-(and 8,9)dichloro-S-(Z-dimethylaminoethyl)-5,1 1-

dihydroindolo 3,2-c] [2,1] benzothiazine-6,6-dioxide5-(2-dirnethylaminoethyl)-5,11-dihydro-7,8-(and 8,9)-

methylenedioxyindolo [3,2-c] [2,1]benzothiazine- 6,6-dioxide.

Treating 5 (2 dimethylaminoethyl) 5,11-dihydro-8- methoxyindolo[3,2-c][2,l]benzothiazine 6,6 dioxide in ether with glacial acetic acid, thenconcentrating in vacuo and filtering gives the acetate salt.

Example 7 By the procedure of Example 1, using 3,4-dihydro-4-oxosulfostyril and the following substituted phenylhydrazines (which areprepared from the corresponding hydrochloride salts by neutralizing anaqueous solution of the salt with hydrochloric acid, extracting withether and removing the ether from the extracts):

p-bromophenylhydrazine p-tolylhydrazine p-butoxyphenylhydrazine3,4-dimethoxyphenylhydrazine the following intermediates are prepared:

8-bromo-5, 1 l-dihydroindolo [3,2-c] [2, 1] benzothiazine-6, 6-dioxide5-,1l-dihydro-S-methylindolo[3,2-c] [2, 1] benzothiazine-6,6-dioxide8-butoxy-5,l1-dihydroind0lo[3,2-c] [2,1 Jbenzothiazine-6,6-dioxide 5, 11-dihydro-7,8- (and 8 ,9 dimethoxyindolo 3,2-c]

[2,1]benzothiazine-6,6-dioxide.

By the procedure of Example 1, the sodio derivative of each of the aboveintermediates is prepared and reacted withN,N-dimethyl-Z-chloroethylamine to give the following products,respectively:

S-bromo-S (Z-dimethylarninoethyl) -5 ,1 l-dihydroindolo 3,2-c][2,11benzothiazine-6,6-dioxide 5- (Z-dimethylaminoethyl) -5,ll-dihydro-S-methylindolo 3,2-c] [2,1]benzothiazine-6,6-dioxide8-butoxy-5-(Z-dimethylaminoethyl)-5,11-dihydroindolo [3 ,2-c][2,1]benzothiazine-6,6-dioxide S-(Z-dimethylaminoethyl)-5,11-dihydro-7,8- (and 8,9) dimethoxyindolo [3,2-c] [2,1]benzothiazine-6,6-dioxide.

Example 8 By the procedure of Example 1 using 3,4-dihydro-4-oxosulfostyril and 3,4-dihydroxyphenylhydrazine (prepared by refluxing3,4-dimethoxyphenylhydrazine with hydrobromic acid in acetic acid forfour hours then concentrating in vacuo, adding aqueous sodium carbonate,extracting with methylene chloride, concentrating in vacuo andrecrystallizing the residue from alcohol-hexane) the product is5-(2-dimethylaminoethyl)-5,11-dihydro-7,8- (and 8,9) dihydroxyindolof3,2-c] [2,1 benzothiazine-6,6- dioxide. The mixture of isomers isseparated to give the 7,8-dihydroxy and 8,9-dihydroxy compounds bychromatography on alumina using methylene chloride as the solvent.

5 (2 dimethylaminoethyl) 5,11 dihydro 8,9- dihydroxyindolo [3,2-c][2,1]benzothiazine-6,6-dioxide in water is treated with dilutehydrochloric acid and the mixture is heated on a steam bath. Cooling andfiltering gives the hydrochloride salt.

Example 9 To a mixture of 3.41 g. of S-(Z-dimethylaminoethyl)- 5,11dihydroinodolo[3,2-c] [2,11benzothiazine 6,6-dioxide (prepared as inExample 1) in 50 ml. of dimethylsulfoxide and 0.3 g. of sodium hydridein mineral oil is added -1.5 g. of methyl chloride. The resultingmixture is heated at reflux with stirring for 24 hours, then isfiltered, concentrated and poured into water. {Extracting with etherthen drying and concentrating the extracts to dryness, addingether-ethanol and filtering gives 5-(2- dimethylaminoethyl) 5 ,1l-dihydro-l 1-methylindolo[3,- 2-c] [2,1]benzothiazine-6,6-dioxide.

Similarly, using 4.1 g. of butyl bromide in place of'N,N-dimethyl-Z-chloroethylamine in the above procedure, the product is'1l butyl-5-(2-dimethylaminoethyl)-5,11- dihydroindolo [3,2-c][2,1]benzothiazine-6,6-dioxide.

Example 10 By the procedure of Example 2 using N,N-diethyl-3-chloropropylamine, the product is 5-(3-diethylarninopropyl)5,11-dihydroindolo[3,2-c] [2,1]benzothiazine-6,- 6-dioxidehydrochloride.

An aqueous solution of the above prepared salt is neutralized withaqueous sodium hydroxide. Extracting with ether, then drying the etherextracts and removing 5. A compound of the formula:

the ether in vacuo gives 5-(3-diethylaminopropyl)-5,1l-

dihydroindolo 3,2-] [2,1]benzothiazine-6,6-di0xide.

What is claimed is: 1. A compound of the formula: H liq-H o, R s 3 NN(CHz)nN l in which Y is hydrogen, halogen or trifiuoromethyl.

6. A compound according to claim 5 in which Y is in which: hydrogen. Yishydrogen, halogen or trifiuoromethyl; 6 compound accordmg to clam '5 mwhlch Y 18 R is hydrogen or lower alkyl; R and R are lower alkyl; andReferences Clted n is 2 or 3 FOREIGN PATENTS or pharmaceuticallyacceptable, acid addition salts there- 20 247,020 4/ 1960' Australiaof.

2. A compound according to claim 1 in which n is 2. HENRY ULES Examine"-3. A compound according to claim 1 in which Y is J M, 'FORD Assistant Ei hydrogen, R and R are methyl and n is 2.

4. A compound according to claim 1 in which Y is US. Cl. X.R. chloro, Rand R are methyl and n is 2. 260-470, 518, 999

